Every time I try to write, I have very good points and important things to say, but my body always feels otherwise and manages to erase everything I took hours to write. And it’s too difficult and time-consuming to redo everything since most of it was a kind of stream of consciousness endeavor. It’s tragic and very sad because my thoughts., I believe , are important in the conversation, and especially germane to this subject
I understand many of these issues, and the vital importance of empirical research. But it also takes quite a bit of time, and many of us pwMS don’t have years and years of time to wait for clinical trials to play out. This is not a complaint, it’s just a fact. I was Dx'd (diagnosed) with multiple sclerosis in 2002, and I was originally hopeful that science and technology in the new millennium would have concrete answers quite soo. But after
I had my second course of Alemtuzumab last October at Royal London. Honestly, it was fine, just far, far too late; I was extremely glad to have it. So far, I haven't developed any new conditions from it, though my lymphocyte count isn't yet back to anywhere near a normal level. I'm interested in the idea of taking other treatments alongside Alumtuzumab, and would have been willing to be in a trial (and would still be willing, if I have more treatment, which I'm trying to just keep an open mind about.)
Jun 5, 2023·edited Jun 5, 2023Liked by Gavin Giovannoni
This is fascinating academic debate that never seems to mention the patients. We are the ones who have to experience/suffer/endure/be treated for these complications, often for the rest of our lives. Whilst the benefits of alemtuzumab for MS outweigh - for most of us - these risks then taking the drug isn't the issue here.
As these risks after a course of alemtuzumab treatment are well known and in many cases quite quantifiable (Graves for example) to just put them all to one side because there is insufficient Placebo Controlled, Randomised, Clinical Trial evidence at present seems to skirt past the growing body of Real World Evidence. RWE is not a fanciful notion and can be derived from observation.
For example: the Whack-A-Mole trial referred to may only have had 10 participants making it woefully underpowered it is my understanding that c. 400 patients have been treated with this protocol or variations thereof. Apparently, not a single person has had any auto-immune issues related to their alemtuzumab infusion. Acknowledging that there are uncontrollable variables and this is NOT hard scientific method data it makes one wonder why there hasn't been a single incidence. In a cohort of c. 400 there would be an expectation of - taking Graves as an example - at least 1/3 having thyroid issues. Roughly, granted. But not one.
The protocol, in whatever form, was not administered by have-a-go amateurs but by specialist neurologists using drugs that have well-established safety profiles. The question of on or off-license use is a confounding factor in differing countries but should not be used to cloud the discussion about whether this expert-led attempts at 'painting outside the lines' works or not.
Until alemtuzumab regains its popularity as a go-to medicine for MS then there will be relatively little commercial interest in mitigating risks. The academic speculating discussed here has the feeling of an existential debate about the hardest science possible, not the end users.
In the meantime, there are actual people, MS patients, who are going to receive alemtuzumab who I imagine are more than willing to try something to mitigate risks. After all, they already have MS and any of the compounds discussed here are not experimental drugs.
I also understand that a lot of tweaking/playing around etc has been done by various neurologists regarding the pre and post infusion regimes of various steroids, antibiotics, and antivirals all with the aim of reducing reactions to alemtuzumab. It would be interesting to see them collated, compared, and remarked upon by an expert such as yourself.
This is actually about mitigating the long term risks to the alemtuzumab recipients using best efforts. They may not be perfect, they may not be proven beyond a shadow of doubt, they may involve using a known compound off-license (hardly a new thing for medicine when a drug for X has been observed to do Y. Think Viagra, Rogaine, Tecfidera - all eventually re-trialled but used off label initially for their effects on another condition than the initial intended indication) all in an imperfect attempt to reduce the long-term negative effects of something.
Preserving an approach in aspic has rarely been a useful approach. Innovation and discovery has often been achieved by people wishing to push boundaries. RCT is the gold standard but in the meantime the issues don't go away and there is a degree of reputable evidence. Even you had the hypothesis initially!
Hi Gavin, it's Elliot Frohman. Thanks for your comments as always.
I hope you are well. We missed having you at the MS Section of the AAN Chair's INTL Advisory Roundtable. Perhaps another time. You'll be very pleased to know that Tree and I are in discussion with a major benefactor concerning the funding of a randomized, prospective, controlled trial of the Teresa Frohman Whack-A-Mole protocol. Very excited about this, and agree it should be done. At one point we tried to invite you to join us, but never heard back. Best always, Elliot and Tree
Quite a lot (trials / studies) going on in the MS research world - rituximab after Alemtuzumab, BTK inhibitors, Frexalimab, Sizomus, Chariot MS, Octopus, Cambridge remyelination trial…. But nothing from these trials / projects (if positive) will be available for another 5+ years. It’s like being in a desert desperate for water. A mirage appears, but as soon as you get close it moves away. Is there nothing else likely to emerge in a a shorter timeframe? What happened to the Black Swan? Why does the U.K. appear to be doing all the donkey work?
Thank you for writing this - this topic interests me greatly so I’m always watching for your opinion. I wish very much I could try this process but understand the requirements of research practice. I hope the results are favourable & it’s not too late for me to benefit! :)
I'm still hung up on the palifermin behaving the opposite way they expected it to with dramatic negative consequences. Did they give these vulnerable people the first in human palifermin infusions? Yikes.
Good morning, just to add a comment on a secondary autoimmunity, in my case after HSCT. I just got a positive result for anti-NMDA-NR1-Receptor. The result was negative prior to HSCT and the bref EBV activation that had followed HSCT. Wondering if it could be a case of a secondary autoimmunity...will follow-up with doctors here.
I got a rituximab infusion at the end of my HSCT treatment - what is the role of it in this case? I am ignorant to the medicine/science in this respect. Is it a similar idea to prevent secondary autoimmunity after the chemo?
Every time I try to write, I have very good points and important things to say, but my body always feels otherwise and manages to erase everything I took hours to write. And it’s too difficult and time-consuming to redo everything since most of it was a kind of stream of consciousness endeavor. It’s tragic and very sad because my thoughts., I believe , are important in the conversation, and especially germane to this subject
Hi Prof G.
I understand many of these issues, and the vital importance of empirical research. But it also takes quite a bit of time, and many of us pwMS don’t have years and years of time to wait for clinical trials to play out. This is not a complaint, it’s just a fact. I was Dx'd (diagnosed) with multiple sclerosis in 2002, and I was originally hopeful that science and technology in the new millennium would have concrete answers quite soo. But after
I had my second course of Alemtuzumab last October at Royal London. Honestly, it was fine, just far, far too late; I was extremely glad to have it. So far, I haven't developed any new conditions from it, though my lymphocyte count isn't yet back to anywhere near a normal level. I'm interested in the idea of taking other treatments alongside Alumtuzumab, and would have been willing to be in a trial (and would still be willing, if I have more treatment, which I'm trying to just keep an open mind about.)
This is fascinating academic debate that never seems to mention the patients. We are the ones who have to experience/suffer/endure/be treated for these complications, often for the rest of our lives. Whilst the benefits of alemtuzumab for MS outweigh - for most of us - these risks then taking the drug isn't the issue here.
As these risks after a course of alemtuzumab treatment are well known and in many cases quite quantifiable (Graves for example) to just put them all to one side because there is insufficient Placebo Controlled, Randomised, Clinical Trial evidence at present seems to skirt past the growing body of Real World Evidence. RWE is not a fanciful notion and can be derived from observation.
>>
https://en.wikipedia.org/wiki/Real_world_evidence
<<
For example: the Whack-A-Mole trial referred to may only have had 10 participants making it woefully underpowered it is my understanding that c. 400 patients have been treated with this protocol or variations thereof. Apparently, not a single person has had any auto-immune issues related to their alemtuzumab infusion. Acknowledging that there are uncontrollable variables and this is NOT hard scientific method data it makes one wonder why there hasn't been a single incidence. In a cohort of c. 400 there would be an expectation of - taking Graves as an example - at least 1/3 having thyroid issues. Roughly, granted. But not one.
The protocol, in whatever form, was not administered by have-a-go amateurs but by specialist neurologists using drugs that have well-established safety profiles. The question of on or off-license use is a confounding factor in differing countries but should not be used to cloud the discussion about whether this expert-led attempts at 'painting outside the lines' works or not.
Until alemtuzumab regains its popularity as a go-to medicine for MS then there will be relatively little commercial interest in mitigating risks. The academic speculating discussed here has the feeling of an existential debate about the hardest science possible, not the end users.
In the meantime, there are actual people, MS patients, who are going to receive alemtuzumab who I imagine are more than willing to try something to mitigate risks. After all, they already have MS and any of the compounds discussed here are not experimental drugs.
I also understand that a lot of tweaking/playing around etc has been done by various neurologists regarding the pre and post infusion regimes of various steroids, antibiotics, and antivirals all with the aim of reducing reactions to alemtuzumab. It would be interesting to see them collated, compared, and remarked upon by an expert such as yourself.
This is actually about mitigating the long term risks to the alemtuzumab recipients using best efforts. They may not be perfect, they may not be proven beyond a shadow of doubt, they may involve using a known compound off-license (hardly a new thing for medicine when a drug for X has been observed to do Y. Think Viagra, Rogaine, Tecfidera - all eventually re-trialled but used off label initially for their effects on another condition than the initial intended indication) all in an imperfect attempt to reduce the long-term negative effects of something.
Preserving an approach in aspic has rarely been a useful approach. Innovation and discovery has often been achieved by people wishing to push boundaries. RCT is the gold standard but in the meantime the issues don't go away and there is a degree of reputable evidence. Even you had the hypothesis initially!
Hi Gavin, it's Elliot Frohman. Thanks for your comments as always.
I hope you are well. We missed having you at the MS Section of the AAN Chair's INTL Advisory Roundtable. Perhaps another time. You'll be very pleased to know that Tree and I are in discussion with a major benefactor concerning the funding of a randomized, prospective, controlled trial of the Teresa Frohman Whack-A-Mole protocol. Very excited about this, and agree it should be done. At one point we tried to invite you to join us, but never heard back. Best always, Elliot and Tree
Quite a lot (trials / studies) going on in the MS research world - rituximab after Alemtuzumab, BTK inhibitors, Frexalimab, Sizomus, Chariot MS, Octopus, Cambridge remyelination trial…. But nothing from these trials / projects (if positive) will be available for another 5+ years. It’s like being in a desert desperate for water. A mirage appears, but as soon as you get close it moves away. Is there nothing else likely to emerge in a a shorter timeframe? What happened to the Black Swan? Why does the U.K. appear to be doing all the donkey work?
Thank you for writing this - this topic interests me greatly so I’m always watching for your opinion. I wish very much I could try this process but understand the requirements of research practice. I hope the results are favourable & it’s not too late for me to benefit! :)
I'm still hung up on the palifermin behaving the opposite way they expected it to with dramatic negative consequences. Did they give these vulnerable people the first in human palifermin infusions? Yikes.
Good morning, just to add a comment on a secondary autoimmunity, in my case after HSCT. I just got a positive result for anti-NMDA-NR1-Receptor. The result was negative prior to HSCT and the bref EBV activation that had followed HSCT. Wondering if it could be a case of a secondary autoimmunity...will follow-up with doctors here.
I got a rituximab infusion at the end of my HSCT treatment - what is the role of it in this case? I am ignorant to the medicine/science in this respect. Is it a similar idea to prevent secondary autoimmunity after the chemo?